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Proc Natl Acad Sci U S A. 2018 Aug 21;115(34):E8007-E8016. doi: 10.1073/pnas.1805437115. Epub 2018 Aug 2.

Incomplete penetrance for isolated congenital asplenia in humans with mutations in translated and untranslated RPSA exons.

Author information

1
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065.
2
Helix, San Carlos, CA 94070.
3
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065; bebo283@rockefeller.edu casanova@rockefeller.edu.
4
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France.
5
Imagine Institute, Paris Descartes University, 75015 Paris, France.
6
Laboratory of Protein and Nucleic Acid Chemistry, The Rockefeller University, New York, NY 10065.
7
Pediatric Hematology, University Hospital of Marseille, 13005 Marseille, France.
8
Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Manchester University Hospitals NHS Foundation Trust Manchester Academic Health Sciences Centre, Manchester M13 9WL, United Kingdom.
9
Division of Evolution and Genomic Sciences, School of Biological Sciences, The University of Manchester, Manchester M13 9NT, United Kingdom.
10
Department of Pediatrics, Insular Maternity and Child University Hospital Center, 35016 Las Palmas de Gran Canaria, Spain.
11
National Geographic Society, Washington, DC 20036.
12
INSERM U1163, 75015 Paris, France.
13
Pediatric Hematology-Immunology and Rheumatology Unit, Necker Hospital for Sick Children, Assistance Publique - Hôpitaux de Paris (AP-HP), 75015 Paris, France.
14
College of France, 75231 Paris, France.
15
French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Hospital for Sick Children, AP-HP, 75015 Paris, France.
16
Pediatric Immunology, Dr. Behcet Uz Children's Hospital, 35210 Izmir, Turkey.
17
Division of Infectious Diseases, University of Nebraska Medical Center, Omaha, NE 68198.
18
Department of Legal Medicine, University Hospital Center Farhat Hached, Sousse, Tunisia.
19
Department of Pediatrics, University Hospital Center Zagreb, 10 000 Zagreb, Croatia.
20
Department of Pediatric Pneumology, Immunology and Intensive Care, Charité - Berlin University Hospital Center, 10117 Berlin, Germany.
21
Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan City 33302, Taiwan.
22
Department of Clinical Biochemistry and Immunology, Addenbrooke's Hospital, Cambridge University Foundation Hospitals NHS Trust, Cambridge CB2 0QQ, United Kingdom.
23
Department of Pediatrics, Infectious Diseases and Internal Medicine, Robert Debré Hospital, AP-HP, 75019 Paris, France.
24
Molecular Genetics, Great Ormond Street Hospital, London WC1N 3JH, United Kingdom.
25
Medical Genetics Dr. Staber & Kollegen Laboratory, 93051 Regensburg, Germany.
26
Pediatric Immunology, Cruces University Hospital, 48903 Barakaldo-Vizcaya, Spain.
27
Medical Genetics Department, University Hospital of Nantes, 44000 Nantes, France.
28
Department of Immunology and Rheumatology, Hospital de Pediatría J. P. Garrahan, 1249 Buenos Aires, Argentina.
29
Department of Immunology, The Children's Memorial Health Institute, 04-730 Warsaw, Poland.
30
Center for the Study of Primary Immunodeficiencies, Pediatric Immuno-Hematology Unit, Necker Children's Hospital, AP-HP, 75015 Paris, France.
31
Oxford Vaccine Group, Department of Paediatrics, Oxford Children's Hospital, University of Oxford, Oxford OX4 2PG, United Kingdom.
32
Department of Immunology, University Hospital of Gran Canaria Doctor Negrin, 35010 Las Palmas de Gran Canaria, Spain.
33
Pediatric Oncology and Hematology, University Hospital of Nantes, 44000 Nantes, France.
34
Department of Immunology, Labor Berlin GmbH, 13353 Berlin, Germany.
35
Berlin-Brandenburg Center for Regenerative Therapies, 13353 Berlin, Germany.
36
Pediatric Immunology, Great Ormond Street Hospital, London WC1N 3JH, United Kingdom.
37
Department of Microbiology and Immunology, KU Leuven, BE-3000 Leuven, Belgium.
38
Department of Pediatrics, KU Leuven, BE-3000 Leuven, Belgium.
39
Institute for Human Genetics, University of California, San Francisco, CA 94143.
40
Program in Craniofacial Biology, University of California, San Francisco, CA 94131.
41
Eli and Edythe Broad Center of Regeneration Medicine & Stem Cell Research, University of California, San Francisco, CA 94131.
42
Department of Orofacial Sciences, University of California, San Francisco, CA 94143.
43
Department of Anatomy, University of California, San Francisco, CA 94143.
44
Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065.

Abstract

Isolated congenital asplenia (ICA) is the only known human developmental defect exclusively affecting a lymphoid organ. In 2013, we showed that private deleterious mutations in the protein-coding region of RPSA, encoding ribosomal protein SA, caused ICA by haploinsufficiency with complete penetrance. We reported seven heterozygous protein-coding mutations in 8 of the 23 kindreds studied, including 6 of the 8 multiplex kindreds. We have since enrolled 33 new kindreds, 5 of which are multiplex. We describe here 11 new heterozygous ICA-causing RPSA protein-coding mutations, and the first two mutations in the 5'-UTR of this gene, which disrupt mRNA splicing. Overall, 40 of the 73 ICA patients (55%) and 23 of the 56 kindreds (41%) carry mutations located in translated or untranslated exons of RPSA. Eleven of the 43 kindreds affected by sporadic disease (26%) carry RPSA mutations, whereas 12 of the 13 multiplex kindreds (92%) carry RPSA mutations. We also report that 6 of 18 (33%) protein-coding mutations and the two (100%) 5'-UTR mutations display incomplete penetrance. Three mutations were identified in two independent kindreds, due to a hotspot or a founder effect. Finally, RPSA ICA-causing mutations were demonstrated to be de novo in 7 of the 23 probands. Mutations in RPSA exons can affect the translated or untranslated regions and can underlie ICA with complete or incomplete penetrance.

KEYWORDS:

RPSA; incomplete penetrance; isolated congenital asplenia; ribosomopathy; spleen

PMID:
30072435
PMCID:
PMC6112730
DOI:
10.1073/pnas.1805437115
[Indexed for MEDLINE]
Free PMC Article

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